The most outstanding characteristic of MHC class II molecules is their extensive polymorphism. This polymorphism allows a population to ensure its survival by maximizing the possibility of generating antigenic peptides derived from infectious agents or dysfunctional cells. The structure of the class II MHC protein is characterized by the presence of a peptide-binding groove running the length of the molecule. Polymorphic amino acid residues are associated predominantly with the groove, suggesting heavy selection for variability in this part of the protein. The current view of the interaction of MHC class II and antigenic peptide is based on binding pockets in the MHC which accept side chains of amino acid "anchor" residues on the peptide. All the identified pockets are polymorphic. The investigator will test the hypothesis that rules for peptide binding to any MHC class II molecule can be defined by examining each point of interaction in isolation and in combination. The examination will utilize a "reversion" approach, in which a structural feature changed by a polymorphism leads to loss of function. The physico-chemical nature of the interaction can then be understood if function can be regained by a compensating change in the peptide. The investigator will start by making amino acid substitutions within the pockets of the MHC molecule and work outward, in order to determine whether peptide binding is merely a sum of the anchor residue contributions, or whether this interaction is more complex. The same rules will be applied to other interactions between class II MHC and accessories to antigen presentation, specifically the class II-associated invariant chain (Ii) and HLA-DM. The results obtained are expected to provide a clearer understanding of the interactions of peptide with all the different class II alleles, which would be beneficial for vaccine generation and peptide antagonist design.